Alternative Names: MAFP, [Methyl Arachidonyl Fluorophosphonate; Methylphosphonofluoridic acid 5,8,11,14-eicosatetraenyl ester
Chemical Name: Methylphosphonofluoridic acid 5,8,11,14-eicosatetraenyl ester.
Cytoplasmic Phospholipase A2 mechanism of action and its relationship to Phospholipase C
Description: Methoxy arachidonyl fluorophosphonate, commonly referred as MAFP, is an irreversible active site-directed enzyme inhibitor that inhibits nearly all serine hydrolases and serine proteases. It inhibits phospholipase A2 (PLA2) and fatty acid amide hydrolase with special potency, displaying IC50 values in the low-nanomolar range.
Why should we be interested in PLA2 inhibition & MAFP?
Over the last quarter century, phospholipases have been an increasingly researched subject, particularly PLA2. The enzymatic pathway with which this protein is involved has been implicated in a number of inflammatory and cancerous conditions, and it would therefore be advantageous to develop an inhibitor for this protein. Intracellular phospholipase A2 is activated through a G-protein signaling cascade, and is linked to phospholipase C. Diacylglycerol is a cleavage product of phospholipase C, and it activates protein kinase C. Protein Kinase C then initiates a signaling cascade that results in the activation of MAPK. MAPK phosphorylates PLA2, and this active phospholipase cleaves intracellular membrane lipids to form a lysolipid and a fatty acid. The fatty acid is often arachidonic acid, and it is this pathway that is associated with disease.
It should also be noted that while it is the arachidonic acid pathway that is linked to many of these conditions, the other cleavage product, a lysophospholipid, has also been linked to disease. Once formed by PLA2 , arachadonic acid can enter at least three different pathways, dependent on the subsequent enzyme or directly decrease the transcription rate of stearoyl-CoA desaturase 1 and glucose transporter 4. These endpoints have been linked to asthma, rheumatoid arthritis, atherosclerosis, obesity, and diabetes (8). It is largely the formation of ecosonoids by arachidonic acid that leads to these inflammatory problems (9).
MORE SPECIFIC PRODUCT INFORMATION ON MAFP.
MAFP, methyl arachidonoylfluorophosphonate, is an esterase inhibitor, linoleoyl homolog that induces platelet-activating factor (PAF) accumulation1. MAFP is a selective, active-site directed, Phospholipase Inhibitor, irreversible inhibitor of cPLA2 (IC50=5Î¼M) and Ca2+-independent iPLA2 (IC50=0.5Î¼M). 2. The latter comprise cPLA2 and iPLA2, which are both inhibited by MAFP4, 5.
MAFP is a Potent, irreversible inhibitor of fatty acid amide hydrolase (FAAH) (IC50=2.5nM), 800 -fold more potent than AACOCF3 Irreversible CB1 receptor antagonist in rat brain membrane (IC50=20nM). MAFP also inhibited neutrophil PAF acetylhydrolase activity and MAFP proved to be the most robust inhibitor of this type. Indeed, quiescent monocytes, like neutrophils, accumulated PAF when treated with MAFP, so PAF accumulation subsequent to disruption of its continual hydrolysis is not a response specific to neutrophils.
PAF activates all cells of innate immune system at picomolar concentrations through a single receptor6,7.
PAF is not normally present as a circulating lipid mediator; rather, it is produced by stimulated
inflammatory cells, and a few select other cell types, as a critical component of the coordinated acute inflammatory response.
o Product number: M-1247
o APPEARANCE: Colorless to light yellow oil Molecular Weight.
o CAS NUMBER: [188404-10-6]
o CHEMICAL FORMULA: C21H36FO2P
o M.W.: 370.5 Da
o PURITY: >98% BY TLC & HPLC.
o CELL PERMEABLE: YES
o SOLUBILITY: SOLUBLE IN ETHANOL 50MG/ML; DMSO 50 MG/ML. Prepared solutions stable 2
months, stored under argon gas at =-20°C. Keep dry.
o SOLID STATE STABILITY: 24months from date of manufacture. o PUBCHEM #: 10429254
Inhibitors of Brain Phospholipase A2 Activity: Their Neuropharmacological Effects
and Therapeutic Importance for the Treatment of Neurologic Disorders Akhlaq A. Farooqui, Wei-Yi Ong, and Lloyd A. Horrocks. Pharmacol. Rev., Sep 2006; 58: 591 - 620., http://pharmrev.aspetjournals.org/content/58/3/591.full.pdf
2. CANCER BIOMARKER:
Biological Roles of Alpha-Fetoprotein During Pregnancy and Perinatal
Development. Gerald J. Mizejewski. Exp Biol Med, Jun 2004; 229: 439 - 463. http://ebm.rsmjournals.com/content/229/6/439.full.pdf
3. CANCER BIOMARKER
beta-Fetoprotein as a Biologic Response Modifier: Relevance to Domain and Subdomain Structure. G. J. Mizejewski Exp Biol Med, Sep 1997; 215: 333 - 362.
Alpha-fetoprotein Structure and Function: Relevance to Isoforms, Epitopes, and
Conformational Variants. Gerald J. Mizejewski. Exp Biol Med, May 2001; 226: 377 - 408. http://ebm.rsmjournals.com/content/215/4/333.full.pdf.
Endocannabinoid-Mediated Control of Synaptic Transmission
Masanobu Kano, Takako Ohno-Shosaku, Yuki Hashimotodani, Motokazu Uchigashima, and Masahiko Watanabe
Physiol Rev, Jan 2009; 89: 309 - 380. http://physrev.physiology.org/content/89/1/309.full?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexacttitle= and&andorexacttitleabs=and&fulltext=mafp&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&fdate=1/1/1990&resour cetype=HWCIT.
1. INFLAMMATION AND IMMUNOPHARMACOLOGY
Balsinde, J., M. A. Balboa, P. A. Insel, and E. A. Dennis. 1999. Regulation and inhibition of phospholipase A2. Annu. Rev. Pharmacol. Toxicol. 39: 175189.
2. INFLAMMATION AND IMMUNOPHARMACOLOGY:
Intracellular PAF catabolism by PAF acetylhydrolase counteracts continual PAF synthesis Jiawei Chen, Lili Yang, Jason M. Foulks, Andrew S. Weyrich, Gopal K. Marathe, and Thomas M. McIntyre J. Lipid Res., Nov 2007; 48: 2365 - 2376.
The transfer of VLDL-associated phospholipids to activated platelets depends upon cytosolic phospholipase A2 activity
Salam Ibrahim, Catherine Calzada, Val©rie Pruneta-Deloche, Michel Lagarde, and Gabriel Ponsin
J. Lipid Res., Jul 2007; 48: 1533 - 1538.
4. INFLAMMATION AND IMMUNOPHARMACOLOGY:
Neutrophil Adherence to Bladder Microvascular Endothelial Cells following Platelet-Activating Factor Acetylhydrolase Inhibition
Suzanne M. Vinson, Alice Rickard, Jan S. Ryerse, and Jane McHowat; J. Pharmacol. Exp. Ther., Sep 2005; 314: 1241 - 1247.
5. RESPIRATORY INFECTIONS:
ExoU-induced procoagulant activity in Pseudomonas aeruginosa-infected airway cells
M. C. Plotkowski, L. F. P. Feliciano, G. B. S. Machado, L. G. Cunha, Jr, C. Freitas, A. M. Saliba, and M. C. de Assis. Eur. Respir. J., Dec 2008; 32: 1591 - 1598.
Prescott, S. M., G. A. Zimmerman, D. M. Stafforini, and T. M. McIntyre. 2000. Platelet-activating factor and
related lipid mediators. Annu. Rev. Biochem. 69: 419-445.
7. Ishii, S., T. Nagase, and T. Shimizu. 2002. Platelet-activating factor receptor. Prostaglandins Other Lipid
Mediat. 68-69: 599-609.
Ex Vivo Imaging of Fatty Acid Amide Hydrolase Activity and Its Inhibition in the Mouse Brain
Sherrye T. Glaser, S. John Gatley, and Andrew N. Gifford
J. Pharmacol. Exp. Ther., Mar 2006; 316: 1088 - 1097
2. CELLULAR MICROBIOLOGY: PATHOGEN-HOST CELL MOLECULAR INTERACTIONS:
Phospholipase A2 Functions in Pseudomonas aeruginosa- Induced Apoptosis Susanne Kirschnek and Erich Gulbins. Infect. Immun., Feb 2006; 74: 850 - 860.
3. INFLAMMATION: Cytosolic phospholipase A2 activation induced by S1P is mediated by the S1P3 receptor in lung epithelial cells
Li-Yuan Chen, Grzegorz Woszczek, Sahrudaya Nagineni, Carolea Logun, and James H. Shelhamer
Am J Physiol Lung Cell Mol Physiol, Aug 2008; 295: L326 - L335
Identification of a Novel Endocannabinoid-Hydrolyzing Enzyme Expressed by Microglial Cells
Giulio G. Muccioli, Cong Xu, Emma Odah, Eiron Cudaback, Jose Antonio Cisneros, Didier M. Lambert, Maria Luiz Lopez Rodriguez, Sandra Bajjalieh, and Nephi Stella. J. Neurosci., Mar 2007; 27: 2883 - 2889
5. MECHANISMS OF SIGNAL TRANSDUCTION:
Feed Forward Cycle of Hypotonic Stress-induced ATP Release, Purinergic Receptor Activation, and Growth Stimulation of Prostate Cancer Cells. Rajender Nandigama, Manju Padmasekar, Maria Wartenberg, and Heinrich Sauer. J. Biol. Chem., Mar 2006; 281: 5686 - 5693
Group V secretory phospholipase A2 plays a pathogenic role in myocardial ischaemia reperfusion injury. Toshiaki Yano, Daisuke Fujioka, Yukio Saito, Tsuyoshi Kobayashi, Takamitsu Nakamura, Jun-ei Obata, Kenichi Kawabata, Kazuhiro Watanabe, Yosuke Watanabe, Hideto Mishina, Shun Tamaru, and Kiyotaka Kugiyama. Cardiovasc Res, May 2011; 90: 335 - 343.
7. INFLAMMATION AND IMMUNOPHARMACOLOGY:
A Cyclooxygenase Metabolite of Anandamide Causes Inhibition of Interleukin-2 Secretion in Murine Splenocytes
Cheryl E. Rockwell and Norbert E. Kaminski. J. Pharmacol. Exp. Ther., Nov 2004; 311: 683 - 690
8. REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY:
Late-Gestation Rat Myometrial Cells Express Multiple Isoforms of Phospholipase A2 That Mediate PCB 50-Induced Release of Arachidonic Acid with Coincident Prostaglandin Production
Kelly Brant and Rita Loch Caruso. Toxicol. Sci., Nov 2005; 88: 222 - 230.
9. MEMBRANES: PROTEIN-LIPID INTERACTIONS AS DETERMINANTS OF FUNCTION:
Effect of acylation in the activity of secretory phospholipase A2 acting on human erythrocyte Carol Linnette Gonzalez, Ileabett Echevarra, Orestes Quesada, and Reginald Morales
FASEB J, Mar 2006; 20: A60
10. PROTEIN MODIFICATION AND TURNOVER:
Acylation of Secretory Phospholipases A2 Alter the Catalytic Activity on Erythrocyte Membrane Carol Gonzalez, Ileabett Echevarra, Edwin V¡zquez, Elizabeth Restituyo, Krystal Morales, Alfredo Erazo, Orestes Quesada, and Reginald Morales. FASEB J, Apr 2007; 21: A1019
11. THERAPEUTIC TARGETS AND MECHANISMS IN CANCER:
Cannabinoid receptor-independent actions of HU210 upon the viability and mobility of PC3 prostate cancer cells. Christopher John Fowler, Sui Chu Chung, and Emma Persson. FASEB J, Apr 2009; 23: 761.6.
13. PROTEIN-LIPID INTERACTIONS:
A Phospholipid Substrate Molecule Residing in the Membrane Surface Me-diates Opening of the Lid Region in Group IVA Cytosolic Phospholipase A2
John Edmund Burke, Yuan-Hao Hsu, Virgil L Woods, Jr., Jr., and Edward A Dennis. FASEB J, Apr 2009; 23: 873.1.
14. GENE EXPRESSION AND EPIGENETIC REGULATION IN MICROENVIRONMENT:
Abstract 4275: PLA2 activities in human epithelial ovarian cancer ascites
Yan Xu, Qingchun Cai, Zhenwen Zhao, Caryl J. Antalis, Libo Yan, Ali H. Hamed, Frederick B. Stehman, Jeanne M. Schilder, and Giuseppe Del Priore. Cancer Res., Apr 2012; 72: 4275.
Cytosolic phospholipase A2 mediates mechanical stretch-induced apoptosis via caspase-3 in human renal proximal tubular epithelial (HK-2) cells. Larry D Alexander. FASEB J, Apr 2012; 26: 1065.2
Elevated and secreted phospholipase A2 activities as new potential therapeutic targets in human epithelial ovarian cancer
Qingchun Cai, Zhenwen Zhao, Caryl Antalis, Libo Yan, Giuseppe Del Priore, Ali Hassan Hamed, Frederick B. Stehman, Jeanne M. Schilder, and Yan Xu. FASEB J, Aug 2012; 26: 3306 - 3320.
17. MEMBRANE TRAFFICKING:
Cholesterol transport from late endosomes to the Golgi regulates t-SNARE trafficking, assembly, and function.
Meritxell Reverter, Carles Rentero, Sandra Vil de Muga, Anna Alvarez-Guaita, Vishwaroop Mulay, Rose Cairns, Peta Wood, Katia Monastyrskaya, Albert Pol, Francesc Tebar, Joan Blasi, Thomas Grewal, and Carlos Enrich. Mol. Biol. Cell, Nov 2011; 22: 4108 - 4123.
18. EXPERIMENTAL MYOCARDIAL INFARCTION:
Abstract 15081: Group V Secretory Phospholipase A2 Plays a Role in Myocardial Ischemia Reperfusion Injury Through Cytosolic Phospholipase A2.
Toshiaki Yano, Kenichi Kawabata, Yukio Saito, Kazuhiro Watanabe, Yosuke Watanabe, Hideto Mishina, Shun Tamaru, Junei Obata, and Kiyotaka Kugiyama. Circulation, Nov 2010; 122: A15081.
19. PREVENTION RESEARCH 2: MODEL SYSTEMS AND BIOMARKERS 1:
Modest activity of alpha-fetoprotein (AFP)-based genetic immunotherapy in a spontaneous hepatocarcinogenesis model.
Lana Y. Schumacher, Dan D. Vo, Sharla K. Owens, Vivian B. Dissette, Begonya Comin-Anduix, Lisa H. Butterfield, Antoni Ribas, and James S. Economou. AACR Meeting Abstracts, Apr 2006; 2006: 161
20. OX1 Orexin/Hypocretin Receptor Signaling through Arachidonic Acid and Endocannabinoid Release Pauli M. Turunen, Maria H. J., and Jyrki P. Kukkonen. Mol. Pharmacol., Aug 2012; 82: 156 - 167
Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes
Myoung Sook Han, Sun Young Park, Koei Shinzawa, Sunshin Kim, Kun Wook Chung, Ji-Hyun Lee, Choon Hyuck Kwon, Kwang-Woong Lee, Joon-Hyoek Lee, Cheol Keun Park, Woo Jin Chung, Jae Seok Hwang, Ji-Jing Yan, Dong-Keun Song, Yoshihide Tsujimoto, and Myung-Shik Lee. J. Lipid Res., Jan 2008; 49: 84 - 97
22. RESEARCH ARTICLES:
PGE2 release is independent of upregulation of Group V phospholipase A2 during long-term stimulation of P388D1 cells with LPS. Ursula A. Kessen, Ralph H. Schaloske, Daren L. Stephens, Karin Killermann Lucas, and Edward A. Dennis. J. Lipid Res., Nov 2005; 46: 2488 - 2496
23. MEMBRANE TRAFFICKING:
cPLA2 and EHD1 interact and regulate the vesiculation of cholesterol-rich, GPI-anchored, protein- containing endosomes. Bishuang Cai, Steve Caplan, and Naava Naslavsky
24. GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL:
The Prostaglandin E2 Type 4 Receptor Participates in the Response to Acute Oxidant Stress in Airway Epithelial Cells. Christina L. Jones, Tiesong Li, and Elizabeth A. Cowley
J. Pharmacol. Exp. Ther., May 2012; 341: 552 - 563. Mol. Biol. Cell, May 2012; 23: 1874 - 1888.
25. RESEARCH ARTICLES:
Modification of LDL with human secretory phospholipase A2 or sphingomyelinase promotes its arachidonic acid-releasing propensity. Janne Oestvang, Dominique Bonnefont-Rousselot, Ewa Ninio, Jukka K. Hakala, Berit Johansen, and Marit W. Anthonsen J. Lipid Res., May 2004; 45: 831 â€“ 838
26. CELLULAR IMMUNOLOGY AND IMMUNE REGULATION:
Ginger Phenylpropanoids Inhibit IL-1Î² and Prostanoid Secretion and Disrupt Arachidonate- Phospholipid Remodeling by Targeting Phospholipases A2 Andreas Nievergelt, Janine Marazzi, Roland Schoop, Karl-Heinz Altmann, and Jrg Gertsch; J. Immunol., Oct 2011; 187: 4140 - 4150
The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis
FranÃ§ois Chouinard, Julie S. Lefebvre, Pauline Navarro, Line Bouchard, Claudine Ferland, M©lanie Lalancette- H©bert, David Marsolais, Michel Laviolette, and Nicolas Flamand; J. Immunol., Mar 2011; 186: 3188 - 3196.
Introduction of phospholipids to cultured cells with cyclodextrin
Ville Kainu, Martin Hermansson, and Pentti Somerharju; J. Lipid Res., Dec 2010; 51: 3533 - 3541
29. RESEARCH ARTICLES:
Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins
Caroline Subra, David Grand, Karine Laulagnier, Alexandre Stella, G©rard Lambeau, Michael Paillasse, Philippe De Medina, Bernard Monsarrat, Bertrand Perret, Sandrine Silvente-Poirot, Marc Poirot, and Michel Record
J. Lipid Res., Aug 2010; 51: 2105 - 2120
The measurement of lysosomal phospholipase A2 activity in plasma. Akira Abe, Robert Kelly, and James A. Shayman; J. Lipid Res., Aug 2010; 51: 2464 - 2470.
31. CELLULAR IMMUNOLOGY AND IMMUNE REGULATION:
Mycobacterium tuberculosis Activates Human Macrophage Peroxisome Proliferator-Activated Receptor Linking Mannose Receptor Recognition to Regulation of Immune Responses
Murugesan V. S. Rajaram, Michelle N. Brooks, Jessica D. Morris, Jordi B. Torrelles, Abul K. Azad, and Larry S. Schlesinger; J. Immunol., Jul 2010; 185: 929 - 942
Blockade of 2-Arachidonoylglycerol Hydrolysis by Selective Monoacylglycerol Lipase Inhibitor 4- Nitrophenyl 4-(Dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) Enhances Retrograde Endocannabinoid Signaling
Bin Pan, Wei Wang, Jonathan Z. Long, Dalong Sun, Cecilia J. Hillard, Benjamin F. Cravatt, and Qing-song Liu J. Pharmacol. Exp. Ther., Nov 2009; 331: 591 - 597.
33. Golgi-associated cPLA2 Regulates Endothelial Cellâ€“Cell Junction Integrity by Controlling the Trafficking of Transmembrane Junction Proteins
Elsa Regan-Klapisz, Vincent Krouwer, Miriam Langelaar-Makkinje, Laxman Nallan, Michael Gelb, Hans Gerritsen, Arie J. Verkleij, and Jan Andries Post; Mol. Biol. Cell, Oct 2009; 20: 4225 - 4234.
34. RESEARCH ARTICLES:
The tumor suppressor gene H-Rev107 functions as a novel Ca2+-independent cytosolic phospholipase A1/2 of the thiol hydrolase type
Toru Uyama, Jun Morishita, Xing-Hua Jin, Yasuo Okamoto, Kazuhito Tsuboi, and Natsuo Ueda
J. Lipid Res., Apr 2009; 50: 685 - 693.
35. CANCER PREVENTION:
Licofelone, a dual COX/5-LOX inhibitor, induces apoptosis in HCA-7 colon cancer cells through the mitochondrial pathway independently from its ability to affect the arachidonic acid cascade Simona Tavolari, Massimiliano Bonaf, Marina Marini, Carla Ferreri, Giovanna Bartolini, Elisa Brighenti, Sonia Manara, Vittorio Tomasi, Stefan Laufer, and Tiziana Guarnieri
Carcinogenesis, Feb 2008; 29: 371 - 380.